Despite several decades of clinical research aimed at developing better therapeutic approaches, lung cancer is still the number one cause of cancer-related death in the United States. In order to develop effective preventive and therapeutic modalities, we must first identify intracellular targets that control the transformation of human bronchial epithelial (HBE) cells and maintain the survival of lung cancer cells. Toward this goal, we have demonstrated that the phosphatidylinositol 3-kinase (PI3K)-dependent pathway is activated in bronchial premalignancy and in a subset of the most common histologic subtype of lung cancer, non-small cell lung cancer (NSCLC). Further, we found that the survival of NSCLC cells is dependent upon activation of PI3K- and mitogen-activated protein kinase kinase-4 (MKK4)-dependent pathways, which cooperate to maintain NSCLC cell survival. Thus, we hypothesize that the PI3K-dependent pathway is a potentially important target in lung cancer prevention and that combined inhibition of PI3K- and MKK4-dependent pathways will be effective in lung cancer therapeutics. In this R01 application, we propose to further explore their cooperative effect in the transformation of HBE cells (Aim 1), the mechanisms by which these pathways maintain cell survival (Aim 2), and the role of AKT in an animal model of lung tumorigenesis (Aim 3). We chose to focus this application on AKT as a mediator of PI3K-dependent signaling because of clear evidence that AKT is sufficient to mediate the transforming effects of PI3K. Through these efforts we hope to gain insights into the basic mechanisms by which HBE cells undergo malignant transformation and NSCLC cells maintain their survival in order to develop strategies for future clinical trials in lung cancer prevention and therapeutics. [unreadable] [unreadable]